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Glucocorticoids: binding affinity and lipophilicity
Journal of Pharmaceutical Sciences
|October 1, 1986
Summary
Steroid modifications alter glucocorticoid receptor binding affinity and lipophilicity. Hydroxyl groups increase affinity, while acetate esters decrease it, impacting drug design for glucocorticoid receptor interactions.
Area of Science:
- Biochemistry
- Molecular Pharmacology
- Dermatology
Background:
- The glucocorticoid receptor (GR) plays a crucial role in cellular responses.
- Understanding steroid-ligand interactions with GR is vital for therapeutic development.
- Keratinocytes express functional GR, relevant for skin conditions.
Purpose of the Study:
- To determine the relative binding affinities of 35 steroids for the GR.
- To correlate binding affinity with steroid lipophilicity.
- To investigate how structural modifications affect GR binding and lipophilicity.
Main Methods:
- Competitive binding assays using radiolabeled dexamethasone or hydrocortisone.
- Measurement of steroid lipophilicity via partition coefficients (1-octanol/aqueous buffer).
- Analysis of 35 different steroid structures and their GR binding characteristics.
Main Results:
- Hydroxyl group substitutions (17 alpha-OH, 21-OH) decreased lipophilicity and increased GR affinity.
- Acetate ester substitutions (17 alpha-OAc, 21-OAc) increased lipophilicity and decreased GR affinity.
- Longer ester chains (valerate) increased both lipophilicity and affinity, but 21-esters had lower affinity than parent alcohols.
Conclusions:
- Steroid structure significantly influences both lipophilicity and GR binding affinity.
- Specific substitutions can modulate GR interaction, offering potential for targeted drug design.
- A correlation between binding affinity and lipophilicity was observed for 17 alpha- and 21-ester series.